DESCRIPTION (adapted from the application) African Americans carry a 3-6 fold increased risk of developing nephropathy as a complication of diabetes mellitus (DM), essential hypertension (HTN), and many other etiologies of renal disease. Although an increased frequency and severity of HTN and socioeconomic factors that limit health care probably contribute, multiple observations indicate that alternative factors are also involved. Fields ranging from epidemiology and therapeutic trials to molecular biology and genetics indicate that the renin-angiotensin system (RAS) contributes to the risk of nephropathy via mechanisms that include but go beyond HTN, perhaps involving the contribution of the RAS to growth and repair, hyperplasia, and hypertrophy. Our proposal is based on several unanticipated observations. First, in healthy African Americans, age-adjusted renal plasma flow (RPF) was substantially less than in Caucasians, assessed in an identical protocol. Moreover, despite a high salt diet, African Americans displayed an enhanced renal vasodilator response to angiotensin-converting enzyme (ACE) inhibition with captopril, which enhanced renal vascular responsiveness to angiotensin II (Ang II). Also, blacks do not increase their RPF when changing to a higher salt intake. This pattern--which clearly differs from that in Caucasians and is similar to our preliminary observations in patients with DM suggests activation of the RAS. Second, in our non-insulin-dependent DM (NIDDM) patients, our preliminary data suggest a range of hitherto unrecognized RAS abnormalities reflecting inappropriate activation and autonomous renin release. Most surprising is the paradoxical extreme RAS activation at the renal tissue level in Type II DM patients with very low plasma renin activity (PRA) and nephropathy. Evidence for a functional contribution comes from hemodynamic measurements made during pharmacological interruption of the RAS with ACE inhibitors and Ang II antagonists, and during Ang II infusion. In Type II DM, race is a critical determinant of risk. Third, we have made observations which indicate that acute hyperglycemia activates the intrarenal renin system and induces striking Ang II-dependent vasoconstriction. Fourth, we have evidence that the risk of advanced nephropathy in Type I DM is related to genetic variability in the eNOS gene. Our hypothesis is that the increase in risk of nephropathy represents an interaction between predisposition to polymorphic genes and environmental factors. Our goal in this study is to explore preliminary evidence that RAS activation and the combination with other polymorphic genes accounts for many Type II DM features involving renal risk and racial differences in risk.